Systems and Methods for Delivering Drugs to Selected Locations Within the Body

ABSTRACT

A transvascular system for delivering a drug to a tissue region from a blood vessel includes a catheter having a distal portion with puncturing, orientation, drug delivery, and imaging elements. The puncturing element is deployable for penetrating the vessel wall to access the tissue region. The orientation element has a predetermined relationship with the puncturing element, the imaging element detecting the location of the orientation element with respect to the tissue region to orient the puncturing element. The catheter is percutaneously introduced into the vessel, the puncturing element is oriented towards the tissue region, the puncturing element is deployed to access the tissue region, and the drug is delivered to the tissue region. An ablation device may also be deployed to create a cavity or fluid reservoir in the tissue region for receiving the drug therein, or an indwelling catheter may be advanced into and left in the tissue region.

This application is a continuation-in-part of applications Ser. Nos.08/730,327 and 08/730,496, both filed Oct. 11, 1996, the disclosures ofwhich are expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods fordelivering substances into a body, more particularly to systems andmethods that use the cardiovascular system as a conduit to deliverdrugs, such as therapeutic drugs, genes, growth factors and the like,directly to selected tissue regions within the body, and mostparticularly to systems and methods that deliver drugs from the venoussystem transvascularly to selected remote tissue regions.

BACKGROUND

It is often desirable to deliver drugs into a patient's body to treatmedical conditions. In particular, a variety of drug therapies areavailable for treating the coronary system, either alone or incombination with more invasive procedures. Such therapies may includedelivering substances, such as nitroglycerin, epinepharin, or lydocaine,endocardially or into the pericardial space to treat the coronarysystem. In addition, heparin, hirudin, ReoPro™ or other anti-thromboticcompounds may be infused into blood vessels associated with the coronarysystem, such as occluded coronary arteries, or elsewhere in thecardiovascular system. More recently, gene therapy, e.g. introducinggenetic material, and growth factor therapy, e.g. introducing proteins,cells or vectors including angiogenic growth factors, have beendemonstrated to provide potential benefits in treating ischemic hearttissue and other regions of the coronary system, for example, bystimulating growth of neovascular conduits, which may evolve into newblood vessels.

In current medical therapy, one method of delivering such drugs involvespercutaneously introducing an infusion catheter into the patient'scardiovascular system. A distal portion of the catheter is directed to adesired endovascular location, for example into a coronary artery, and adrug is infused into the artery at a location reachable intraluminally.The catheter may include a lumen extending between its proximal anddistal ends, the distal end having one or more outlet ports. A source ofthe drug, such as a syringe, may be connected to the proximal end andthe drug delivered through the lumen and outlet port(s) into the desiredlocation.

For example, a “bolus,” i.e. a relatively large single dose of a drug,may be delivered using an infusion catheter into an artery, which may beabsorbed by the arterial wall, the surrounding tissue, and/or may becarried by blood flow to regions further downstream from the deliverylocation. Alternatively, the drug may be infused continuously orintermittently into the artery for an extended period of time.

The infusion catheter often includes a porous perfusion balloon on itsdistal end, the interior of which communicates with the outlet port(s)and lumen in the catheter. Pores or holes in the balloon may be arrangedto direct the drug from the balloon towards the arterial wall to improvepenetration into the arterial wall and attempt to localize delivery. Inaddition, the infusion catheter may be provided with an electrode and/ora heating element on or in the balloon to cause electroporation or toheat the surrounding tissue to further improve localized delivery.

Some devices try to enhance localized delivery of drugs usingionophoresis. A first electrode may be provided within a perfusionballoon, and a second electrode provided on an external region of thepatient's body near the artery. When direct current is applied betweenthe electrodes, a drug carried by an electrically charged compound maybe directed along the path of current flow from the internal electrodetowards the external electrode in an attempt to improve penetration ofthe drug into the arterial wall and surrounding tissue.

As an alternative to perfusion balloons and/or infusion catheters, adrug may be embedded in or deposited on a catheter, e.g. in the catheterwall, the wall of a non-porous balloon on the catheter, and/or a coatingon the catheter. After the distal end is directed to a desired location,the drug may be delivered into an artery, for example, by ionophoresissimilar to that described above or by simply allowing the drug todissolve within the artery.

In an alternative to delivering a bolus of drugs, it is often desirableto provide sustained delivery of a drug within the cardiovascularsystem. For example, a pair of occlusion balloons disposed along thelength of a catheter may be provided on an infusion catheter that may bedirected endovascularly to a desired location within an artery. Theballoons may be inflated to isolate a section of the artery betweenthem, and a drug may be delivered into the isolated section in anattempt to provide sustained delivery to the isolated section. Theballoons are then deflated, and the catheter removed from the body.

Drug delivery devices may also be implanted within an artery to providesustained delivery. For example, U.S. Pat. No. 5,628,784 issued toStrecker discloses an expandable annular sleeve that may be deployedwithin an artery. A small quantity of drugs may be introduced betweenthe sleeve wall and the surrounding arterial wall to directly contactthe arterial wall, where they may be absorbed over an extended period oftime. PCT Publication No. WO 95/01138 discloses a porous ceramic sleevethat may be implanted directly in tissue, such as in bone marrow or asurgically created pouch. The sleeve includes drugs within a cellculture or matrix in the sleeve, which may, for example, be dispersed inthe pores of the sleeve or be provided in a cylindrical insert.

In addition, a number of extravascular methods have also been suggested.For example, drugs may be injected directly into a desired tissueregion, typically by accessing the region through a chest incision.Alternatively, a polymer gel or drug-soaked sponge may be attached tothe outside of a vessel or to a portion of the endocardium to beabsorbed by the contacted region. In addition, the pericardial space mayhave substances injected directly into it, for example by accessing thepericardial sac through a chest incision. Such methods may provideeither single dose or sustained delivery of drugs to the heart.

One of the problems often associated with existing methods is dilutionor “wash-out” of the drug during delivery. Dilution may substantiallyreduce the effectiveness of a therapy by preventing sufficientquantities of the drug from reaching a desired region. For example,during endovascular delivery using an infusion catheter, the drug may bediluted as it travels through the arterial wall or may be carrieddownstream through the artery to other regions within the coronarysystem and/or elsewhere in the body.

The volume of drug may be increased to offset dilution concerns, butthis may exacerbate concerns about undesired dissemination of the drug.For example, certain therapeutic drugs, genetic material and growthfactors may have undesired global side effects. Releasing a drug intothe blood stream may allow it to be carried throughout the coronarysystem or elsewhere in the body where it may have significant adverseeffects. Similar adverse effects may result from pericardial delivery,in which a drug may be absorbed throughout the coronary system, ratherthan only in a desired local region.

Further, many conventional methods are unable to provide effectivesustained delivery, which may be important to the success of certaintreatments, such as gene or growth factor therapy, where it may bedesirable to maintain a drug in a desired region for hours, days or evenlonger. Occlusion systems, such as the dual occlusion balloon catheter,or the implantable sleeves described above, may be able to isolate aregion of an artery for some sustained treatments.

Such occlusion devices, however, may introduce additional risksassociated with obstructing flow within the coronary system for extendedperiods of time. In particular, if the arterial system is occluded formore than short periods of time during treatment, substantial damage mayoccur, for example, ischemia and possibly infarction of tissuedownstream from the occluded region.

Conventional endovascular systems may also be inadequate to accesscertain tissues in need of treatment. For example, infusion cathetersmay be unable to pass through an occluded region of an artery to treatischemic tissue downstream of the region. Further, it may be hazardousto direct an endovascular device through a stenotic region because ofthe risk of releasing embolic material from the arterial wall, which maytravel downstream and become embedded in other vessels or even travel tovital organs, such as the brain, where they may cause substantial damageor even death.

More invasive methods, such as direct injection of drugs, may provideaccess to otherwise unattainable regions. Such methods, however,typically involve open-chest or other invasive surgical procedures, andthe costs and risks associated with them.

Accordingly, there is a need for improved systems and methods ofdelivering drugs to desired locations within the body with greaterprecision, reduced global side-effects, and/or that substantially reducethe problems of the previous systems and methods.

SUMMARY OF THE INVENTION

The present invention is directed to systems and methods for deliveringa drug to a tissue region within a patient's body, and in particular tosystems and methods that use the venous system as a conduit to deliver adrug directly to a remote tissue region, or to facilitate acatheter-based intervention. “Drug” as defined herein includes anytherapeutic drugs, genetic materials, growth factors, cells, e.g.myocites, vectors carrying growth factors, and similar therapeuticagents or substances that may be delivered within a patient's body forany therapeutic, diagnostic or other procedure. In one aspect of thepresent invention, a transvascular catheter system is provided thatgenerally includes a catheter, a drug delivery element, an orientationelement, and possibly a puncturing element and/or an imaging element.The catheter has a proximal portion and a distal portion adapted forinsertion into a blood vessel, and defines a periphery and alongitudinal axis. The puncturing element is deployable from the distalportion in a predetermined relationship with the circumference orperiphery of the catheter, and includes a distal tip adapted topenetrate a wall of a blood vessel to access a tissue region beyond thewall of the blood vessel. The drug delivery element is provided on thedistal portion for delivering a drug to the tissue region, and anorientation element is also provided on the distal portion in apredetermined relationship with the periphery of the catheter and thepuncturing element.

Preferably, the catheter has a peripheral opening at a predeterminedlocation on the periphery of the distal portion through which thepuncturing element may be deployed, and a needle lumen communicatingwith the peripheral opening for receiving the puncturing elementtherethrough. The needle lumen includes a deflecting element adapted todirect the distal tip substantially transversely with respect to thelongitudinal axis when the puncturing element is deployed.

The system may include an imaging element adjacent the orientationelement for detecting the location of the orientation element withrespect to the tissue region. For example, the imaging element may be anultrasound transducer which may be received in a lumen extending betweenthe proximal and distal portions of the catheter.

In a first preferred embodiment, the puncturing element is a needle andthe drug delivery element is a lumen in the needle. The needle mayinclude an array of outlet ports for providing a predetermined flowpattern of fluid into the tissue region accessed by the needle. Inaddition, at least a portion of the needle may be a conductive materialelectrically coupled to a proximal end of the puncturing element forcoupling the needle to a source of electric current. Alternatively, thepuncturing element may be a plurality of needles deployable frompredetermined locations on the distal portion to provide a selectedtrajectory pattern into the tissue region.

In a second preferred embodiment, the puncturing element includes aguide wire, and the drug delivery element is deployable over the guidewire. For example, the drug delivery element may be an infusioncatheter, possibly including a perfusion balloon. Alternatively, thedrug delivery element may include an indwelling catheter which isdelivered over the guide wire, either before or after removal of thetransvascular catheter. The drug delivery element may include a firstelectrode thereon adapted to be electrically coupled to a secondelectrode. When direct current is directed between the first and secondelectrodes, fluid from the drug delivery element may be ionophoreticallydirected from the drug delivery element towards the second electrode.Alternatively, the drug delivery element may be an osmotic surface onthe transvascular catheter, the infusion catheter or the indwellingcatheter.

To assist in orienting the system during use, the orientation elementpreferably has an asymmetric configuration aligned with the puncturingelement, for example with the peripheral opening through which thepuncturing element may be deployed. In a first preferred embodiment, theorientation element is a “cage” structure that includes a plurality ofstruts extending axially along the distal portion. Preferably, a firststrut is provided at a location in direct axial alignment with theperipheral opening, and a pair of struts are provided opposite the firststrut to “point” towards the peripheral opening. Alternatively, theorientation element may include a marker that may be imaged using anexternal imaging system, and preferably a pair of markers disposedopposite one another on the periphery, either instead of or preferablyin addition to the “cage” structure.

A transvascular catheter system in accordance with the present inventionmay be used to deliver a drug to a tissue region within a patient'sbody, such as into the myocardium or a coronary artery from the coronaryvenous system, in a method which may proceed as follows. The distalportion of the catheter may be percutaneously introducing into a bloodvessel, and directed endovascularly to a vessel location adjacent to thetissue region selected for treatment. The puncturing element may beoriented towards the selected tissue region, and deployed to access thetissue region. A drug may then be delivered with the drug deliveryelement to the tissue region.

Preferably, when the puncturing element is being oriented, theorientation element is imaged, for example with an imaging elementadjacent the orientation element. The imaging element is preferablyoperated to obtain an image of the orientation element in relation tothe surrounding tissue, thereby identifying the orientation of thepuncturing element because of the predetermined relationship between theorientation element and the puncturing element. Preferably, the imagingelement is an ultrasound transducer within the catheter that may be usedto obtain image slices along a plane substantially normal to thelongitudinal axis of the catheter, the images preferably including theorientation element, the selected tissue region and/or other landmarkswithin the vessel or the surrounding tissue.

Where the puncturing element is a drug delivery needle, the needle maybe deployed, penetrating a wall of the blood vessel and entering thetissue region, and the drug may be delivered through a lumen in theneedle. Alternatively, a drug delivery element may be deployed incombination with the puncturing element. For example, an infusioncatheter may be advanced over the puncturing element to the tissueregion, and the drug infused therethrough, or through a porous balloonon the infusion catheter which may be inflated within the tissue region.

Prior to delivering the drug, a “mapping” procedure may be used toensure that the drug will be delivered as desired into the specifictissue region selected for treatment. For example, a radiographic agentmay be delivered using the drug delivery element to observe the flowthereof with respect to the selected tissue region. Once it has beenconfirmed that the radiographic agent flows as desired into the selectedtissue region, the drug may then be introduced, thereby possiblyavoiding misdelivery of what are often quite expensive drugs.Alternatively, a radiographic agent and the like may be mixed with thedrug to track the flow of the drug within the body, particularly withrespect to the selected tissue region.

In another preferred method, the transvascular catheter system may beused to create a drug reservoir directly in a selected tissue region.For example, a tissue ablation device may be provided that is deployablein combination with the puncturing element for creating a cavity in anextravascular tissue region. The ablation device may be advanced overthe puncturing element into the tissue region, and an ablation elementthereon activated to create a cavity or drug reservoir within the tissueregion. A drug may then be introduced into the drug reservoir, which maybe sealed from the vessel, for example by introducing a sealant ormatrix into the drug reservoir. Alternatively, the drug reservoir may beformed by removing a portion of the tissue region, for example with acutting instrument or similar mechanical device.

In a further alternative, the transvascular system may be used tofacilitate an indwelling catheter-based intervention. The catheter maybe introduced into a vessel, and then the puncturing element may beoriented and deployed into a tissue region, such as interstitial tissueor another blood vessel. A guide wire may be advanced into the tissueregion, and the transvascular catheter may then be removed, leaving theguide wire in place, possibly anchored to the tissue region. A thin,floppy catheter may be tracked over the guide wire into the tissueregion, and left in place within the tissue region, and the wire may beremoved. The indwelling catheter may be taped, ported or otherwisesecured to the patient depending upon the length of time therapy isdesired. The tissue region may then be accessed via the indwellingcatheter to deliver a drug to the tissue region as often as desired.

In another aspect of the present invention, an implantable drugreservoir system may be used to provide sustained delivery of a drugwithin the cardiovascular system of a patient. Generally, the systemincludes a reservoir device having an expandable frame and a flexiblemembrane thereon. The frame is adapted to expand between a collapsedcondition for insertion into a blood vessel and an enlarged conditionfor engaging a wall of the blood vessel. The frame is preferably biasedtowards the enlarged condition, and also preferably defines alongitudinal axis and a periphery.

The flexible membrane is attached to the frame to define a reservoirtherein, and includes a porous region, such as a semi-permeablematerial, that is preferably disposed along the periphery of the frame.A drug, possibly together with an anti-coagulant, is provided within thereservoir that is adapted to pass through the porous region of themembrane. An end region of the membrane may be penetrable, for exampleby a needle, to facilitate in situ filling of the reservoir.

In an alternative embodiment of the implantable drug reservoir system, areservoir device similar to that described above may be provided with aseptum dividing the reservoir within the membrane into first and secondreservoir regions. The membrane preferably includes an osmotic regioncommunicating with the first reservoir region, and the porous region ofthe membrane preferably communicates with the second reservoir region.

During use, the reservoir device may be introduced along a blood vesselto a location adjacent a selected tissue region, for example within acoronary vein adjacent to an occluded artery or ischemic myocardialtissue. The reservoir device may be deployed and expanded, preferablyautomatically, to its enlarged condition to anchor the reservoir devicewithin the blood vessel. A drug may be prefilled within the reservoir oran injection device may be advanced to penetrate the membrane of thereservoir device and fill the reservoir in situ with the drug.

The drug may then permeate, seep, or otherwise pass through the porousregion, preferably directly into the wall of the vessel and thesurrounding tissue region. If desired, the reservoir may be refilled insitu using an injection device as the drug is dispersed or otherwiseabsorbed by the tissue. Similarly, a reservoir device having a septumpanel may deliver the drug in the second reservoir region to the tissueregion as the first reservoir region osmotically fills, thereby slowlyforcing or “pumping” the drug through the porous region.

In another preferred embodiment of an implantable drug reservoir system,a pair of expandable devices, similar to the reservoir devices may beused. The expandable devices, or endovascular “blockers,” include anexpandable frame, and a non-porous membrane covering at least one end ofthe frame, and preferably extending along at least a portion of theperiphery.

The first blocker is advanced in a collapsed condition along the bloodvessel to a location adjacent the selected tissue region. The firstblocker is then expanded to its enlarged condition, thereby sealing theblood vessel at the location from fluid flow along the blood vessel. Thesecond blocker is then advanced in a collapsed condition along the bloodvessel to the location, preferably adjacent the first blocker. Thesecond blocker is then expanded to its enlarged condition, therebyfurther sealing the blood vessel at the location from fluid flow alongthe blood vessel. The second blocker is preferably deployed apredetermined distance from the first blocker, thereby defining asubstantially sealed drug reservoir within the blood vessel itselfbetween the blockers.

A drug may be introduced into the blood vessel adjacent the firstblocker, either before or after the second blocker is deployed. Forexample, the second blocker may include an end panel only on the endaway from the drug reservoir between the blockers, and an injectiondevice may be advanced to penetrate the end panel. The drug may then beintroduced into the second blocker and consequently into the drugreservoir between the blockers. Thus, a section of a blood vessel may beisolated and a drug delivered therein to provide sustained and localizeddelivery of the drug into the selected tissue region surrounding thevessel.

Accordingly, a principal object of the present invention is to provide asystem and method for precisely delivering a drug to a selected tissuelocation within the body.

It is also an object to provide a system and method for providingsustained delivery of a drug to a desired location within the body overan extended period of time.

It is also an object to provide a system and method for creating areservoir within the body for receiving a drug to provide sustaineddelivery to a desired tissue region within the body.

It is also an object to provide a system and method that use thecardiovascular system as a conduit to deliver a drug to a selectedremote tissue region within the body with substantial precision.

It is also an object to provide a system and method for delivering adrug transvascularly using the venous system as a conduit to access aselected remote tissue region.

More particularly, it is specifically an object of the present inventionto use the coronary venous system to provide access to a highly remotetissue region of the body, e.g. heart tissue.

Other objects and features of the present invention will become apparentfrom consideration of the following description taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a cross-sectional view of a transvascular catheter system inaccordance with one aspect of the present invention.

FIGS. 1B and 1C are side views of a handle on the catheter for thetransvascular catheter system of FIG. 1A.

FIG. 1D is a cross-sectional view of the distal portion of a catheterfor the transvascular catheter system of FIG. 1A.

FIG. 1E is a side view of a needle assembly for the transvascularcatheter system of FIG. 1A.

FIG. 2 is a cross-sectional view of the distal portion of thetransvascular catheter system of FIG. 1, showing the needle assemblydeployed into a remote blood vessel.

FIG. 3A is a cross-sectional view of the transvascular catheter systemand surrounding heart tissue of FIG. 2, taken along line 3-3 using aninternal imaging element, showing artifacts directing the cathetertowards another blood vessel.

FIG. 3B is a cross-sectional view of the transvascular catheter systemand surrounding heart tissue, similar to FIG. 3A, but showing artifactsdirecting the catheter towards the myocardium of the heart.

FIG. 4 is a side view detail of a catheter, showing a preferredembodiment of an externally detectable orientation element in accordancewith the present invention.

FIG. 5A is a side view of an alternative embodiment of the distalportion, including a plurality of needle assemblies.

FIG. 5B is a side view of another alternative embodiment of the distalportion, including a dual lumen needle assembly.

FIG. 5C is another alternative embodiment of the distal portion,including a plurality of outlet ports for providing a predetermined flowpattern.

FIG. 5D is another alternative embodiment of the distal portion,including a feedback sensor on the needle assembly.

FIG. 6 is a cross-sectional view of another preferred embodiment of atransvascular catheter system in accordance with the present invention,including a guide wire assembly and a drug delivery catheter deployedinto a remote tissue region.

FIG. 7 is a perspective view of an implantable port assembly for usewith a transvascular catheter system in accordance with the presentinvention.

FIG. 8 is a cross-sectional view of another preferred embodiment of atransvascular catheter system, including a guide wire assembly and anablation device.

FIG. 9A is a side view of an implantable endovascular drug reservoirdevice in accordance with the present invention.

FIG. 9B is a side view of another embodiment of an implantableendovascular drug reservoir device, including a recrossable end panel.

FIGS. 9C and 9D are side views of the implantable endovascular drugreservoir device of FIG. 9B, showing an injection device for filling thereservoir.

FIG. 10 is a cross-sectional side view of the drug reservoir device ofFIG. 9A, deployed within a vein adjacent to a stenotic region of anartery.

FIG. 11 is a side view of an alternative embodiment of an implantableendovascular drug reservoir device in accordance with the presentinvention.

FIG. 12 is a side view of another implantable system in accordance withthe present invention for creating a drug delivery reservoir, shownwithin a vein adjacent to a stenotic region of an artery.

FIG. 13 is a cross-sectional view of a transvascular catheter system inaccordance with the present invention delivered downstream of a stenoticregion in a blood vessel.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Turning now to the drawings, FIGS. 1A-1E and 2 show a preferredembodiment of a transvascular catheter system 10 in accordance with thepresent invention for delivering a drug to a selected remote tissueregion within a body from a blood vessel near the tissue region. Thesystem 10 generally includes a catheter 12, a puncturing element 14, anorientation element (e.g. a “cage” structure 16 described below), and animaging element 18.

The catheter 12 may be an elongate member having substantially flexibleand/or semi-rigid sections, and defining a circumference or periphery 20and a longitudinal axis 22 between proximal and distal ends 24, 26. Thecatheter 12 includes a proximal portion 28 having a handle 50 and adistal portion 30 having a size and shape to facilitate insertion into ablood vessel.

An IVUS lumen 32 extends through the catheter 12 from an IVUS entry port52 in the handle 50 to a tip member 44 on the distal portion 30 forreceiving the imaging element 18. A needle lumen 36 also extends from aneedle entry port 54 in the handle 50 to a peripheral opening 34 in thedistal portion 30 for receiving the puncturing element 14. The needlelumen 36 includes a deflecting element or ramp 48 adjacent theperipheral opening 34.

The catheter 12 may include an extruded dual lumen catheter encapsulatedwithin an outer jacket (not shown), and/or may have a proximal portionthat is substantially more rigid than a distal portion. For example, inthe preferred embodiment shown in FIG. 1A, the catheter 12 includes aproximal portion 12 a, an intermediate portion 12 b, and a distalportion 12 c, each having a dual lumen catheter segment and an outerjacket segment. The rigidity or Durometer of the dual lumen catheter andouter jacket segments of the proximal portion 12 a is preferably 63 and70, while the remaining segments preferably have a Durometer of 40.Additional information on the construction of the catheter 12, e.g. itsmaterial composition, its size and shape, may be found in co-pendingapplications Ser. Nos. 08/730,327 and 08/730,496, both filed on Oct. 11,1996, and in PCT Application No. PCT/US97/01459, filed on Jan. 31, 1997,the disclosures of which are expressly incorporated herein by reference.

The orientation element is preferably a marker “cage” structure 16including a plurality of elongate members or struts 38, 40 on the distalportion 30 located distally of the peripheral opening 34. The struts 38,40 preferably extend distally from the distal end 26 substantiallyparallel to the longitudinal axis 22 to the proximal edge 42 of the tipmember 44, thereby further defining the IVUS lumen 36. The struts 38, 40preferably define a peripheral window 46, which may be covered by amaterial substantially transparent to the imaging element 18 or mayremain open to blood flow. The struts 38, 40 are preferablysubstantially rigid tubular members, such as hypotubes, which arereflective to the imaging element 18, i.e. will produce a reflection orartifact when the imaging element 18 is operated, and/or may besubstantially opaque to an external imaging apparatus (not shown).

Preferably, the struts 38, 40 have an asymmetrical configuration aboutthe periphery 20 that has a predetermined relationship with the locationof the peripheral opening 34. More preferably, a first strut 38 islocated on the periphery 20 directly distally from the location of theperipheral opening 34. A pair of struts 40 are then positioned oppositethe first strut 38, thereby defining an isosceles triangle or TRI-POINT™cross-sectional configuration, with the first bar 38 at the top of thetriangle. Thus, the orientation element 16 may “point” circumferentiallytowards the location of the peripheral opening 34 on the periphery 20,i.e. towards the location from which the puncturing element 14 may bedeployed, as described further below.

In an alternative embodiment shown in FIGS. 4A and 4B, the orientationelement may include one or more externally visible markers 116 placed atone or more predetermined locations on the periphery 20 of the catheter12. The markers 116 define a pattern to facilitate detection of theorientation of the distal portion 30 about the longitudinal axis 22 withthe aid of an external imaging apparatus. For example, the markers 116may be formed from a radiopaque material visible using a fluoroscopicimaging system. Preferably, a pair of fluoroscopic markers 116 a, 116 bare provided on the periphery 20 that uniquely indicate the rotationalorientation of the peripheral opening 34, such as the “bulls-eye”arrangement shown. Further discussion of such markers may be found inU.S. Ser. No. 08/730,327 filed Oct. 11, 1996, the disclosure of which isexpressly incorporated herein by reference. Although the transvascularcatheter system 10 may include both internal and external markers 16,116 on the catheter 12, preferably only one marker or orientationelement is necessary to effectively orient the puncturing element 14.

Returning to FIGS. 1A-1E and 2, the tip member 44 attached to the struts38, 40 has an annular shape formed from a substantially flexiblematerial to further define the IVUS lumen 32. The tip member 44 ispreferably tapered to facilitate insertion into and direction along thelumen of a blood vessel, and is substantially coaxial with the IVUSlumen 32 in the catheter 12 to facilitate the introduction of a guidewire or other instrument axially therethrough.

With particular reference to FIGS. 1A-1C, the handle 50 is preferably asubstantially rigid member including the IVUS entry port 52, the needleentry port 54, and a needle lumen flush port 58 in communication withthe needle lumen 36. The ports 52, 54 and 58 may include one or moreseals to prevent backflow, as will be appreciated by those skilled inthe art. A control and/or locking mechanism 58 is located on the handle50 that includes a needle thumb slide 68 and an adjustable needle stop70 that cooperatively slide along a graduated region 60 of the handle50.

The needle thumb slide 68 may be directed axially along the graduatedregion 60 to deploy the puncturing element 14, as described moreparticularly below. The adjustable needle stop 70 is slidable on thehandle 50 and is securable at a plurality of positions on the graduatedregion 60 of the handle 50. Thus, the adjustable needle stop 70 may belocked at a first position on the graduated region 60, loosened,directed axially to a second position on the graduated region 60, andlocked at the second position to limit the movement of the needle thumbslide 68, and consequently the depth of penetration of the puncturingelement 14.

Turning to FIGS. 1A-1E, the puncturing element 14 is preferably a needleassembly 62 including an elongate tubular body 63 having a puncturingdistal tip 64 and a proximal safety clip 66. The needle assembly 62and/or the distal tip 64 are preferably formed from a shape memoryalloy, such as Nitinol, that is precurved to enhance transversedeployment of the distal tip 64. The distal tip 64 may be inserted intothe needle entry port 54 and directed distally through the needle lumen36 until the safety clip 66 abuts the needle thumb slide 68 on thehandle 50. The needle thumb slide 68 then may be secured to the needleassembly 62, for example with ball detents that extend radially into theneedle lumen 36 from the needle thumb slide 68 (not shown), forcontrolling axial movement of the needle assembly 62.

Preferably, the needle assembly 62 includes a drug delivery lumen 72extending from the safety clip 66 to an outlet 74 in the distal tip 64.The outlet 74 may be a single opening for directing fluid distallybeyond the distal tip 64, or may include a plurality of openings havinga predetermined outlet pattern. For example, as shown in FIG. 5C, thedistal tip 64 may include a closed tip 73 and one or more side openings75 for directing the drug substantially laterally from the distal tip 64into the tissue region. Preferably, the distal tip 64 also has asufficiently small gauge diameter such that the passage 123 between thevessel 102 and the tissue region 100 is substantially self-sealing toprevent escape of the drug from the tissue region back into the vessel102 upon removal of the distal tip 64.

Alternatively, as shown in FIG. 5B, the needle assembly 62 may includedual lumens 78 a, 78 b that extend between a multiple line manifold onthe proximal end (not shown) to two adjacent outlet ports 74 a, 74 b. Adual lumen needle assembly may be useful for delivering a radiographicagent or other compound through one lumen in combination with a drug inthe other. More preferably, the dual lumens may allow two drugs to beindependently injected, which may then react with one another oncewithin the selected tissue region, as will be appreciated by thoseskilled in the art.

The distal tip 64 may also be at least partially conductive, forexample, by providing an electrode thereon (not shown) or by forming thedistal tip 64 from a conductive material such as platinum, gold, orpossibly stainless steel. A conductor, such as an electricallyconductive wire (not shown), may extend proximally from the distal tip64 through the tubular member 63 to the safety clip 66 of the needleassembly 62. A source of electric current may then be coupled to theconductor to enhance absorption of the drug by the tissue region. Forexample, the distal tip 64 may facilitate electroporation, i.e.energizing the distal tip 64 may create microscopic pores in thesurrounding tissue to enhance penetration of the drug therein.

With respect to the imaging element 18, in a first preferred embodimentbest seen in FIG. 2, an intravascular ultrasound (“IVUS”) device 80 isprovided. A conventional ultrasound transducer 82 is provided on thedistal end 84 of the IVUS device 80 that is oriented towards an imagingplane substantially normal to the longitudinal axis 22. The ultrasoundtransducer 82 or a reflector on the IVUS device 80 (not shown) may berotatable about the longitudinal axis 22 to provide ultrasonic imageslices along the imaging plane in a conventional manner, oralternatively, a phased array of ultrasound transducers may be providedto allow imaging along a plane substantially normal to the longitudinalaxis 22, as will be appreciated by those skilled in the art. Furtherinformation on the use of an IVUS device for imaging tissue and othersurrounding landmarks from within a blood vessel may be found in“Transvenous Coronary Ultrasound Imaging—A Novel Approach toVisualization of the Coronary Arteries” by Sudhir et al., the disclosureof which is expressly incorporated herein by reference.

During use, the transvascular catheter system 10 may be used to delivera drug to a selected remote tissue region within a patient's body in thefollowing manner. The catheter 12 may be introduced percutaneously intoa blood vessel in a conventional manner, while the needle assembly 62remains retracted within the needle lumen 36, i.e. while the distal tip64 is positioned within the needle lumen 36 proximal to the deflectingelement 48. The distal portion 30 of the catheter 12 may be directedendovascularly to a vessel location adjacent to a remote tissue regionfor which treatment is selected.

For example, in one preferred method shown in FIGS. 2 and 3A, thecatheter 12 may be directed through the patient's venous system to acoronary vein 102 adjacent to a coronary artery 100 selected fortreatment. In another preferred method shown in FIGS. 6 and 3B thecatheter 12 may be directed to a location within a coronary vein 102adjacent to a selected ischemic region 220 of the myocardium 112 fordelivering a drug therein. Once the desired endovascular location isreached, the catheter 12 may be oriented towards the selected tissueregion using ultrasound imaging with the IVUS device 80, externalimaging, such as fluoroscopy, or both.

Turning to FIGS. 2 and 3A, the IVUS device 80 is shown being used toorient the system 10 for delivering a drug into a coronary artery 100from a nearby coronary vein 102. The distal portion 30 of the catheter12 is directed endovascularly through the venous system, for exampleover a guidewire 86, until it is within the coronary vein 102 andadjacent the selected coronary artery 100. The ultrasound transducer 82may then be operated to provide a cross-sectional image of the region,shown illustratively in FIG. 3A. The resulting image aids the user inorienting the catheter 12 with respect to the tissue surrounding thevein 102, for example to identify landmarks such as the pericardium 109,the endocardium 111, the epicardium 113, and/or the heart chamber 110.Further, because the struts 38, 40 are opaque to the ultrasoundtransducer 82 (not shown in FIG. 3A), they produce artifacts 104, 106 onthe image, thereby providing the orientation of the distal portion 30 ofthe catheter 12 with respect to the surrounding myocardium 112 and theselected coronary artery 100.

More particularly, because of the triangular arrangement of the struts38, 40, their artifacts 104, 106 “point” circumferentially in thedirection of the periphery 20 corresponding to the location of theperipheral opening 34, and consequently in the direction towards whichthe distal tip 64 of the needle assembly 62 will be deployed from thecatheter 12. The catheter 12 may be torqued about its longitudinal axis22 to rotate the distal portion 30, as observed by the artifacts 104,106, until it can be seen that the distal tip 64 of the needle assembly62, i.e. the artifact 104, is directed towards the selected the coronaryartery 100.

The resulting ultrasound image may also be scalable, allowing the userto measure the distance to the selected target region from the catheter12, and thereby determine the precise distance that the distal tip 64 ofthe needle assembly 62 will need to be directed to reach the selectedtissue region. The needle stop 70 on the handle 50 may then be loosened,adjusted along the graduated region 60, and then locked at apredetermined position corresponding to the precise distance.

Once the catheter 12 is properly oriented and the needle stop 70 islocked at the predetermined position, the distal tip 64 of the needleassembly 62 may be deployed from the catheter 12 to penetrate the wall103 of the vessel location 102 and enter the selected tissue region 100.Preferably, the needle thumb slide 68 is directed distally by the user,thereby directing the distal tip 64 against the deflecting element 48and causing the distal tip 64 to deflect radially outward as it exitsthe peripheral opening 34.

Because of the secured position of the needle stop 70 on the handle 50,the needle thumb slide 68 may be quickly advanced distally until itabuts the needle stop 70, thereby puncturing the wall 103 of the vein102 and delivering the distal tip 64 the precise distance, i.e.precisely within the selected target region of the artery 100.Alternatively, it may be desirable to overshoot, i.e. pass apredetermined distance through and beyond the selected target region,and then slowly withdraw the distal tip 64 until it reaches the selectedtissue region.

A drug may then be introduced into the selected tissue region, forexample by connecting a source of the drug such as a syringe (notshown), to the proximal end (not shown) of the needle assembly 62, andinjecting the drug through the lumen 72 and the outlet 74 in the distaltip 64. The distal tip 64 may then be withdrawn back into the needlelumen 36 and the catheter 12 withdrawn from the patient in aconventional manner.

Prior to delivering the drug, a “mapping” procedure may be used toensure that the drug will be delivered as desired into the specifictissue region selected for treatment. For example, a radiographic agentmay be delivered through the outlet 74 in the distal tip 64. The flow ofthe radiographic agent may be observed with respect to the selectedtissue region, for example using fluoroscopy. Once it has been confirmedthat the radiographic agent flows as desired into the selected tissueregion, the drug may then be introduced, thereby possibly avoidingmisdelivery of what are often quite expensive drugs. Alternatively, aradiographic agent and the like may be mixed with the drug to track theflow of the drug within the body, particularly with respect to theselected tissue region.

Turning now to FIG. 6, another preferred embodiment of a transvascularcatheter system 10 for delivering a drug to a remote tissue region 220within the myocardium 112 is shown. Several of the elements are similarto those previously described and consequently have the same referencenumbers and will not be described further. The system 10 of thisembodiment includes a drug delivery element, namely a drug deliverycatheter 214, that may be deployed from the distal portion 30 of thecatheter 12, preferably in combination with the puncturing element 14.

The puncturing element 14 preferably includes a solid needle or guidewire assembly 162, without a lumen but otherwise similar to the needleassembly 62 previously described, over which the drug delivery catheter214 may be deployed. The guide wire assembly 162 may include ananchoring tip (not shown) for fixing the distal tip 164 of the guidewire assembly 162 in the tissue region 220 and/or to facilitateintroduction of instruments, such as the drug delivery catheter 214, tothe tissue region 220.

The drug delivery catheter 214 may include a porous balloon 218 forinfusing the drug in a predetermined pattern within the tissue region220, and generally includes a plurality of lumens extending between itsproximal portion (not shown), and a distal portion 222. The drugdelivery catheter 214 preferably has a guide wire lumen 224 such thatthe drug delivery catheter 214 may be delivered to the tissue region 220over the guide wire assembly 162, and also has a drug delivery lumen(not shown) communicating with a portion, e.g. the interior, of theporous balloon 218. The porous balloon 218 includes a porous region,such as a plurality of holes 226, a permeable membrane and the like,preferably arranged to provide a predetermined flow pattern through theballoon 218 into the tissue region 220.

During use, the catheter 12 may be introduced percutaneously into ablood vessel 102, and oriented with respect to the selected tissueregion 220 (see FIG. 3B). The guide wire assembly 162 may then bedeployed transvascularly to access the selected tissue region 220,similar to the process previously described. The drug delivery catheter214 may then be advanced over the guide wire assembly 162 until itenters the tissue region 220. The balloon 218 may then be inflated,expanding it from a collapsed condition around the drug deliverycatheter 214 to an enlarged condition contacting the surrounding tissue220. The balloon 218 may be inflated simply by introducing a drugthrough the drug delivery lumen, which may then seep through the porousregion 226 and pass into the tissue region 220. Alternatively, thecatheter 214 may include a separate inflation lumen (not shown) throughwhich an inflation media such as saline may be introduced into anon-porous region within the balloon isolated from the porous region, aswill be appreciated by those skilled in the art. In a furtheralternative, the drug delivery element may be a flexible, thin, floppycatheter which may be left behind to serve as an “indwelling”transcutaneous access catheter, as described more particularly below.

In further alternatives, the drug delivery catheter 214 and/or the guidewire assembly 162 may include an electrode or other element (not shown)to enhance penetration of the delivered drug into the tissue region. Forexample, an internal heating element (not shown) may be provided withinthe balloon 218 to heat the fluid therein and/or the surrounding tissue220, which may enhance absorption of the drug delivered into the tissue.Alternatively, an electrode (not shown) may be provided on or within theballoon 218 which may be coupled to an external electrode (not shown).Direct current may then be applied between the electrodes toionophoretically direct drugs from the drug delivery catheter 214 deepinto the surrounding tissue 220. In a further alternative, the distaltip 164 of the guide wire assembly 162 may be formed from anelectrically conductive material such as gold or platinum, or mayinclude an electrode on a portion thereof (not shown), which may becoupled to an external source of electric current via a conductor (notshown) extending proximally through the guide wire assembly 162.

Thus, a transvascular catheter system 10 in accordance with the presentinvention may be used to deliver a single dose or bolus of a drugdirectly and precisely into a selected remote tissue region.Alternatively, the system may be used for sustained delivery by keepingthe distal portion 30 of the catheter 12 and/or the distal tip 64 of theneedle assembly 62 within the blood vessel and/or selected tissue regionfor an extended period of time.

For example, the needle assembly 62 or infusion catheter 214 may be usedto inject a matrix material into a tissue region which may slowlydiffuse a drug into the tissue region. Alternatively, a stent or similarstructure may be delivered into the tissue region, the structureincluding a drug therein that may be released over time.

In addition, to provide sustained delivery and/or a series of treatmentsof a drug, an indwelling catheter (not shown) may be left behind withinthe selected tissue region. For example, the transvascular cathetersystem 10 may be introduced into a blood vessel, and the puncturingelement 14, e.g. the needle assembly 62 or the guide wire assembly 162,may be oriented and deployed within a selected tissue region, such as aninterstitial tissue region or another blood vessel.

A guide wire (not shown) may be advanced into the tissue region, andpossibly anchored in place. The transvascular catheter 12 may bewithdrawn from the blood vessel, leaving the guide wire, and a thin,floppy catheter (not shown), which may be an infusion catheter similarto that previously described or simply a single delivery port device,may be tracked over the guide wire into the tissue region and leftthere. The guide wire may then be removed, and the proximal end (notshown) of the thin, floppy catheter may be secured to the patient, forexample taped or ported (such as using a port assembly such as thatdescribed below) depending upon the length of time therapy is desired.The distal end of the indwelling catheter may then remain in placewithin the tissue region, possibly for extended periods of time, toprovide access whenever needed.

Alternatively, turning to FIG. 7, the transvascular catheter system 10may include an implantable port assembly 350. The port assembly 350includes a body 352 which may be implantable on or beneath the skin ofthe patient, and one or more seals 354. The body includes a hollow hub356 the interior of which communicates with the seal 354 which may beattached to the transvascular catheter system 10, such as the proximalend 24 of the catheter 12 or preferably to an indwelling catheter (notshown).

For example, the catheter 12 shown in FIG. 1 may be percutaneouslyintroduced into a patient's cardiovascular system, and the distalportion 30 may be advanced into a selected vessel, whereupon the distaltip 64 of the needle assembly 62 (not shown in FIG. 7) may be advancedinto a selected remote tissue region, similar to the methods previouslydescribed. The handle 50 (not shown in FIG. 7) may then be removed fromthe proximal end 24 and replaced with the port assembly 350 such thatthe hub 356 may communicate with the needle lumen 36, the IVUS lumen 32,and/or a drug delivery lumen in the indwelling catheter. The portassembly 350 may then be stitched or otherwise implanted onto anaccessible region of the patient's body (not shown).

Whenever it is desired to access the tissue region, an instrument suchas a needle, an infusion device, a sensor and the like (not shown) maybe directed through the seal 354 to communicate with the drug deliveryelement extending to the selected tissue region. For example, duringgene or growth factor therapy, it is often desired to subject theselected tissue region to compounds, such as angiogenic growth factors,for extensive periods of time. The implantable system of the presentinvention facilitates such sustained treatment by allowing the tissueregion to be accessed as often as necessary to maintain a desired levelof growth factor at the selected tissue region.

Turning now to FIG. 8, another preferred embodiment of a transvascularcatheter system 10 in accordance with the present invention is shown,which may be used to create a drug reservoir 224 within a selectedtissue region 220 itself to provide sustained delivery. A catheter 12,similar to that previously described, may be introduced endovascularlyinto a blood vessel 102 until the distal portion 30 is adjacent thetissue region 220. The distal tip 64 of the needle assembly 62 may beoriented and deployed to puncture the wall 103 of the vessel 102 andenter the tissue region 220, using methods similar to those describedabove.

An ablation device 230, such as a radio frequency (RF) device, a laserdevice, and the like, may be advanced over the needle assembly 62 intothe tissue region 220. One or more electrodes 232 or similar elements onthe ablation device 230 may be activated to create a cavity 224 withinthe tissue region 220 in a manner known to those skilled in the art. Theablation device 230 may then be removed, and a drug may be introducedinto the cavity 224 to create a drug reservoir in continuous contactwith the surrounding tissue 220, thereby providing sustained delivery asthe drug is slowly absorbed by the surrounding tissue 220.

As an alternative to ablation of tissue, a non-porous balloon catheter(not shown) may be advanced over the needle assembly 62 into the tissueregion 220. The balloon may be inflated to its enlarged condition tocontact and push aside the surrounding tissue 220, and create a cavity224. No additional treatment of the tissue 220 may be needed to createthe cavity 224, particularly in ischemic tissue which is substantiallynon-resilient as compared to healthy tissue and unlikely to expand backto fill the cavity 224. It is also within the spirit of the presentinvention that other devices, such as cutting, coring or othermechanical instruments, may also be used to remove tissue to create thecavity 224 by being advanced over the needle assembly 62 into the tissueregion 220, as will be appreciated by those skilled in the art.

In addition, it may be desirable to inject a sealant or matrix material,such as collagen or a filament structure (e.g. drug-impregnated suturematerial), into the cavity 224 or into the passage 223 extending betweenthe blood vessel 102 and the cavity 224. Although the distal tip 64 maybe sufficiently small so as to create a self-sealing passage 223,advancement of instruments, such as the drug delivery catheter 214 ofFIG. 6, may dilate the passage 223, which may result in the drug leakingthrough the passage 23 back into the blood vessel 102 from the cavity224. To substantially reduce the risk of this occurring, a sealant,matrix material, or filament (not shown) may be injected into the cavity224 itself, or into the passage 223, for example through a lumen in thedrug delivery element 214 or the needle assembly 62 before or while itis being withdrawn from the cavity 224.

In a further alternative shown in FIG. 5A, the transvascular cathetersystem 10 may include a plurality of needle assemblies 62, similar tothe individual needle assembly described above, to be deployed in apredetermined arrangement along the periphery 20 of the catheter 12.Preferably, the needle assemblies 62 are arranged axially in a row,aligned with the strut of the “cage” structure orientation element (notshown in FIG. 5A). In particular, it may desirable to access an extendedremote tissue region, for example extending substantially parallel to avessel, especially within the myocardium. With a multiple needletransvascular catheter system, a single device may be delivered into avessel and oriented. The array of needles may be sequentially orsimultaneously deployed to inject one or more drugs into the extendedtissue region, thereby providing a selected trajectory pattern.

Other directional drug delivery elements may also be provided within thepresent invention. For example, a catheter having a drug deliveryelement, an orientation element and possibly an imaging element may beprovided similar to those described above. Instead of a needle or guidewire assembly, the distal portion of the catheter may include an osmoticsurface on a portion of the circumference or periphery and extendingaxially along the distal portion (not shown).

The osmotic surface preferably has a predetermined relationship to theorientation element, such that the osmotic surface may be directedcircumferentially towards a selected tissue region, e.g. a specificportion of a vessel wall and/or a tissue region beyond the vessel wall.The catheter may include a balloon or other expandable structure whichmay push the osmotic surface into direct contact with the vessel wall tofurther facilitate delivery. A drug, possibly embedded within theosmotic surface itself or in a chamber beneath the osmotic surface, maythen be delivered with or without ionophoresis or other assisteddelivery mechanism.

Turning to FIG. 13, the systems and methods of the present invention mayalso be used to provide access downstream of an occluded or stenoticregion of a blood vessel, for example to treat a coronary artery orischemic tissue region of the myocardium downstream of an occludedcoronary artery. First, a location downstream of an occluded section 404of a coronary artery 400 may be selected for treatment, and atransvascular catheter device (not shown) percutaneously introduced intothe venous system and advanced until it reaches a coronary vein 402adjacent the selected artery 400. An interstitial passage 406 may becreated between the coronary vein 402 and the coronary artery 400, and aguide wire 410 may be advanced through the interstitial passage 406 intothe coronary artery 400. The guide wire 410 may be substantiallyanchored within the coronary artery 400, for example by embedding thedistal end of the guide wire 410 into the wall of the coronary artery400 (not shown). Further details on the systems and methods forperforming interstitial or transvascular procedures between the venousand arterial systems may be found in co-pending application Ser. Nos.08/730,327 and 08/730,496, both filed Oct. 11, 1996, the disclosures ofwhich are expressly incorporated herein by reference.

A transvascular catheter system 10, similar to those previouslydescribed, may then be advanced over the guide wire 410 along the venoussystem, through the interstitial passage 406 and into the coronaryartery 400 downstream of the occluded region 404, thus withoutdisturbing plaque or otherwise affecting flow through the arterialsystem. It will be appreciated by those skilled in the art that thetransvascular catheter system 10 used to deliver the drug may also beused to create the interstitial passage 406.

The artery 400 itself may then be treated, for example, using the needleassembly 62 of FIG. 1 or the drug delivery catheter 214 of FIG. 6. Adrug may be delivered into the lumen 408 of the artery 400, into thevessel wall 412 and/or the surrounding tissue 414. In addition, one ormore drug reservoirs (not shown) may be created within the surroundingtissue 414, most preferably within myocardial tissue adjacent to acoronary artery, for receiving a drug that may be absorbed by thesurrounding tissue 414 over an extended period of time.

Other useful features may also be included in any of the embodiments ofthe transvascular catheter system 10 in accordance with the presentinvention. For example, the catheter 12 may include one or morestabilizing balloons (not shown) on the distal portion 30, for exampleproximal to the peripheral opening 34. An inflation lumen may beprovided in the catheter 12 to allow an inflation medium, e.g. saline,to be introduced into the stabilizing balloon to substantially anchorthe catheter 12 at a desired location within the blood vessel, i.e. toprevent the catheter 12 from moving axially within the vessel once thedistal portion 30 is adjacent to a remote tissue region selected fortreatment.

In addition, one or more of the elements of the system may include asensor for measuring information relevant to the treatment of theselected tissue region. For example, a pressure sensor may be providedon the catheter 12, the needle assembly 62 and/or the drug deliveryelement. A lumen may extend proximally through the respective element,thereby allowing the user to continuously monitor pressure at or nearthe delivery site. The drug delivery element may also include a flowmeasurement sensor, allowing the amount of drug being delivered to theselected tissue region to be precisely measured.

Other feedback elements may also be provided, for example, athermocouple or other temperature sensor may be provided on systemsincluding ionophoresis electrodes or ablation devices to monitor theamount of heating being experienced by tissue during a procedure.Alternatively as shown in FIG. 5D, the needle assembly 62 or othercomponent may include a feedback element 79 for measuring aphysiological condition. For example, an EKG lead may be included on thedistal tip or otherwise delivered within the selected tissue region,thereby allowing electrical events within the heart to be monitoredduring drug delivery. During treatment, for example, a drug may bedelivered into a tissue region until a desired condition is met, such asuntil the tissue becomes non-tachycardic, or until tachycardia isinduced.

An important aspect of the transvascular catheter system of the presentinvention is the ability to precisely deliver a drug to a selectedremote location within a reference frame, preferably including acircumferential or peripheral component and a radial component. Theorientation element provides the peripheral component because of itspredetermined relationship with the periphery of the catheter and thedrug delivery element. The imaging element preferably provides theradial component by detecting the relationship of the orientationelement to the selected remote location (e.g. the distance betweenthem), or landmarks in a known relationship with the selected remotelocation. Once the location of the selected remote location is knownwithin the reference frame, the drug delivery element may be directedtowards the selected remote location for precise delivery of a drug.

In another aspect of the present invention, FIGS. 9A-9D and 10 show apreferred embodiment of an implantable reservoir device 400 that may beused to provide sustained delivery of a drug to tissue surrounding ablood vessel, preferably within a coronary vein 102 adjacent to ischemicmyocardial tissue 112. The reservoir device 400 includes a substantiallycylindrical frame 402 adapted to expand between a collapsed conditionfor insertion into a blood vessel and an enlarged condition for engaginga wall 103 of the blood vessel 102, and defining a longitudinal axis404.

The frame 402 is sufficiently flexible to expand between the collapsedand enlarged conditions during use without substantial risk of failingor fatiguing, yet sufficiently rigid to anchor the reservoir device 400within the blood vessel 102. Preferably, the frame 402 is resilientlybiased towards the enlarged condition to prevent substantial movement ofthe frame 402 axially within the blood vessel 102. The frame 402 may beformed from a woven mesh of wire of, for example, a shape memory alloysuch as Nitinol, stainless steel, platinum, polymers or other plasticsand the like. The frame 402 may be woven into a criss-cross structure, asinusoidal structure, or may include a pair of expandable ringsconnected by spacers to retain the rings apart axially.

A flexible membrane 408 is attached to the frame 402, preferably to theexterior of frame 402 such that the membrane 408 may enhance afluid-tight seal when pressed against the wall 103 of the vessel 102 bythe frame 402 after deployment. The membrane 408 includes a periphery412 and end panels 414, 416, which together define a sealed reservoir410 within the membrane 408 and the frame 402. The membrane 408 shouldbe substantially flexible, and may be elastic if tension over the frameis preferred, or plastic if a small initial diameter is preferred.Preferred materials include dacron and PTFE, which may also be siliconedipped.

The membrane 408 includes a porous region 418, which is preferablydisposed along at least a portion of the periphery 412 of the membrane408. The porous region 418 may be a permeable or semi-permeable materialbonded or otherwise attached to non-permeable segment(s) of the membrane408. Alternatively, the entire membrane 408 may be formed from anon-permeable material with holes formed through discrete areas todefine the porous region 418.

In addition, as shown in FIGS. 9B and 9C, at least one of the end panels416 may be recrossable, i.e., may be penetrable by a needle 432, butautomatically resealable, to facilitate in situ filling or refilling ofthe reservoir 410, preferably having a concave shape to facilitatepenetration by the needle 432. Alternatively, the reservoir 410 may beprefilled with a drug, possibly together with an anti-coagulant or othercompound, prior to delivery into the blood vessel 422. In addition, thedrug and the pore size of the porous region 418 may have a predeterminedrelationship such that the drug permeates or flows through the porousregion 418 into the surrounding tissue at a predetermined flow rate.

During use, the reservoir device 400 is percutaneously delivered into ablood vessel in its collapsed condition using a delivery device, forexample within a lumen of a delivery catheter or sheath adapted toreceive the reservoir device 400. Alternatively, the frame 402 mayinclude a control hub on one end (not shown), which may be gripped andcompressed radially inward to collapse the frame 402.

Once the reservoir device 400 is in a blood vessel adjacent the targetregion, such as the coronary vein 102 adjacent to the selected tissueregion 112, the reservoir device 400 is deployed from the deliverydevice, for example using a plunger within the delivery catheter lumen(not shown). Preferably, the frame 402 automatically expands to itsenlarged condition, thereby substantially anchoring the device 400 inposition within the vessel 102. The frame 402 may also create asubstantially fluid-tight seal with the wall 103 of the vessel 102, toprevent substantial leakage of fluid delivered through the periphery 412downstream within the vessel 102.

If the reservoir 410 is empty during deployment, for example, to preventrupture of the membrane 408 when the frame 402 is collapsed, a drugdelivery element may be introduced into the vessel 102 to fill thereservoir 410. For example, as shown in FIGS. 9C and 9D, an injectiondevice 430 including a sheath 434 covering a hollow needle 432 may bedelivered endovascularly, or the delivery catheter used to deliver thereservoir device 400 may include an additional drug delivery needlelumen. The needle 432 may be deployed to penetrate the recrossable endregion 416, whereupon the reservoir 410 may be filled by introducing thedrug through the needle 432.

The reservoir device 400 may remain in the vessel 102 for a substantialperiod of time, possibly hours or days, allowing the drug to slowlyabsorb into the wall of the vessel and preferably the surroundingtissue. In addition, the drug delivery element, e.g. the sheath-coveredhollow needle, may be reintroduced into the vessel 423 to refill thereservoir 410, for example using an implantable port assembly similar tothat shown in FIG. 7. Alternatively, the reservoir device 400 mayinclude an electrode (not shown) to enable ionophoresis or otherenhanced delivery. A catheter including a conductor (not shown) may beintroduced into the vessel 102, coupled to the electrode, and thenenergized by an external source of electric current (not shown) for thispurpose.

In an alternative embodiment, shown in FIG. 11, the reservoir device 400may provide an endovascular “pump” for time-release delivery of a drug.In this embodiment, the reservoir device 400 includes a septum panel 420dividing the reservoir 410 into first and second regions 410 a, 410 b.The first end panel 414 of the membrane 408 is an osmotic membrane andthe first reservoir 410 a is filled with a fluid absorbing compound. Theporous region 418 of the membrane 408 communicates only with the secondreservoir 410 b, which is filled with a drug in situ or beforedeployment.

When the reservoir device 400 is deployed within a vessel (not shown),using a procedure similar to that just described, the compound in thefirst reservoir 410 a begins to slowly draw fluid osmotically fromwithin the lumen of the vessel. As this occurs, the septum panel 420 isforced to expand towards the second end panel 416, thereby applying aforce within the second reservoir 410 b, which “pumps” or otherwiseencourages the drug to flow out the porous region 418, and preferablyinto the wall of the vessel.

In other arrangements, instead of the septum panel 420, a cylindricalseptum may be provided, creating an internal first reservoir and anannular second reservoir surrounding the first reservoir (not shown).The area of one or both end panels in contact with the internal firstreservoir may be provided from an osmotic material, thereby creating asimilar flow out of a porous region on the periphery of the membrane incommunication with the annular second reservoir.

Other shapes and configurations of the reservoir device 400 may also beprovided that may be deployed and substantially anchored adjacent aselected tissue region. In addition, a drug reservoir device similar tothose described may be delivered directly into tissue, for example,using one of the transvascular catheter systems previously described, aswill be appreciated by those skilled in the art.

In another preferred embodiment shown in FIG. 12, an implantable systemincluding a pair of endovascular blocker devices 500 may be used tocreate a drug reservoir 508 a within a blood vessel 102 itself, i.e.between the blockers 500 and the wall 103 a of the vessel 102 betweenthem. The blockers 500 preferably include an expandable frame 502 and aflexible membrane 504 attached to the frame 502, similar to thatdescribed above. The membrane 504, however, is preferably non-permeable,although alternatively a permeable periphery (not shown) may be providedto increase the surface area through which the drug may be directedtowards the vessel wall 103.

To create the reservoir 508 a, the first blocker 500 a is deployedwithin a vessel 102 adjacent a selected tissue region, such as astenotic region 105 within an artery 102, using a method similar to thatdescribed above for the reservoir device 400. A drug is introduced intothe vessel lumen 108 a, and a second blocker 500 b is deployed withinthe vessel 102, thereby encapsulating the drug in the lumen 108 abetween the blockers 500 a, 500 b.

Alternatively, the drug may be delivered into the reservoir 508 a afterboth blockers 500 are deployed and in secured within the vessel 102. Forexample, the second blocker 500 b may include a recrossable end panel514 on one end, and an open interior that may communicate directly withthe reservoir 108 a. Thus, an injection needle device (not shown) may beused to inject the drug through the recrossable end panel 514 and intothe reservoir 508 a in situ.

It has been determined clinically that one or more segments of thevenous system, even within the coronary system, may be occluded forextensive periods of time without adversely affecting the performance ofthe coronary system. Accordingly, an implantable reservoir system inaccordance with the present invention may be used to create a reservoirwithin a coronary vein without interfering substantially with the flowof return blood from the myocardium. A drug within the reservoir maythen be absorbed by the vessel wall and surrounding tissue to treatselected tissue regions adjacent the reservoir site.

Of further note, it has been clinically determined that completeocclusion and shutdown of the coronary venous system may not impairnormal operation of the heart. The endocardial veins may take over atleast a portion of the additional venous return. Furthermore, withinthirty minutes of complete occlusion, the Thebesian system, whichincludes capillaries, venals and porous tissue that makes up themyocardium itself, may replace the venous system and return one hundredpercent of the return blood from the myocardium. Thus, the reservoirdevices in accordance with the present invention may be deployed in oneor more regions within the coronary venous system without substantialrisk of adversely affecting coronary blood flow or damaging the tissuesof the coronary system.

While the invention is susceptible to various modifications, andalternative forms, specific examples thereof have been shown in thedrawings and are herein described in detail. It should be understood,however, that the invention is not to be limited to the particular formsor methods disclosed, but to the contrary, the invention is to cover allmodifications, equivalents and alternatives falling within the spiritand scope of the appended claims.

1. A system for delivering a drug towards a tissue region within apatient's body, the system comprising: a catheter having a proximalportion and a distal portion adapted for insertion into a blood vessel,and defining a periphery and a longitudinal axis; an orientation elementon the distal portion in a predetermined circumferential relationshipwith the periphery of the catheter for providing a peripheralorientation of the distal portion about the longitudinal axis; and adrug delivery element on the distal portion for delivering a drug in apredetermined direction with respect to the longitudinal axis, the drugdelivery element being aligned with the peripheral orientation of theorientation element.
 2. The system of claim 1, wherein the drug deliveryelement comprises a needle deployable from the distal portion.
 3. Thesystem of claim 2, wherein the needle is deployable substantiallyradially from the distal portion.
 4. The system of claim 3, furthercomprising a control mechanism on the proximal portion of the catheterlinked to the needle for deploying the needle a precise distanceradially from the distal portion, whereby the needle may be preciselydeployed to a selected region remote from the catheter within areference frame including a peripheral component and a radial component.5. The system of claim 3, further comprising an imaging element adjacentthe orientation element for detecting the relationship of theorientation element with respect to the selected region, therebyproviding the peripheral component and the radial component of theselected region within the reference frame.
 6. The system of claim 1,wherein the drug delivery element comprises an osmotic surface on aportion of the periphery aligned with the peripheral orientation of theorientation element.
 7. A system for delivering a drug to a tissueregion within a patient's body, the system comprising: a catheter havinga proximal portion and a distal portion adapted for insertion into ablood vessel, and defining a periphery and a longitudinal axis; apuncturing element deployable from the distal portion in a predeterminedcircumferential relationship with the periphery of the catheter, andincluding a distal tip adapted to penetrate a wall of a blood vessel toaccess a tissue region beyond the wall of the blood vessel; a drugdelivery element on the distal portion for delivering a drug to thetissue region; and an orientation element on the distal portion in apredetermined relationship with the periphery of the catheter and thepuncturing element.
 8. The system of claim 7, further comprising animaging element adjacent the orientation element for detecting thelocation of the orientation element with respect to the tissue region.9. The system of claim 8, wherein the imaging element comprises anultrasound transducer.
 10. The system of claim 8, wherein the catheterincludes a lumen extending from the proximal portion to the distalportion for receiving the imaging element therein.
 11. The system ofclaim 7, further comprising: a handle on the proximal portion; and acontrol mechanism on the handle linked to the puncturing element forprecisely advancing the puncturing element from the distal portion. 12.The system of claim 7, further comprising a peripheral opening at apredetermined circumferential location on the periphery of the distalportion through which the puncturing element may be deployed.
 13. Thesystem of claim 12, wherein the catheter includes a needle lumencommunicating with the peripheral opening for receiving the puncturingelement therethrough.
 14. The system of claim 13, wherein the needlelumen includes a deflecting element adapted to direct the distal tipsubstantially transversely with respect to the longitudinal axis whenthe puncturing element is deployed.
 15. The system of claim 7, whereinthe puncturing element comprises a needle and wherein the drug deliveryelement comprises a lumen in the needle.
 16. The system of claim 15,wherein the needle includes an array of outlet ports for providing apredetermined flow pattern of fluid into the tissue region accessed bythe needle.
 17. The system of claim 15, wherein the needle includes aplurality of lumens extending therethrough for independently introducinga plurality of drugs.
 18. The system of claim 7, wherein at least aportion of the puncturing element comprises a conductive materialelectrically coupled to a proximal end of the puncturing element forcoupling the puncturing element to a source of electric current.
 19. Thesystem of claim 7, wherein the puncturing element comprises a pluralityof needles deployable from predetermined locations on the distal portionto provide a selected trajectory pattern for the drug delivery element.20. The system of claim 7, further comprising an implantable portassembly including a hub that is attachable to the drug deliveryelement, and a penetrable seal providing a fluid-tight seal with thedrug delivery element, the implantable port assembly being implantablein the patient's body for providing long term access to the tissueregion.
 21. The system of claim 7, wherein the drug delivery elementcomprises an indwelling catheter deployable in combination with thepuncturing element to the tissue region.
 22. The system of claim 7,wherein the puncturing element comprises a guide wire, and wherein thedrug delivery element is deployable over the guide wire.
 23. The systemof claim 22, wherein the drug delivery element comprises an infusioncatheter.
 24. The system of claim 22, wherein the drug delivery elementcomprises a perfusion balloon.
 25. The system of claim 22, wherein theguide wire includes an anchoring tip for fixing the guide wire in thetissue region.
 26. The system of claim 22, wherein the drug deliveryelement includes an anchoring tip for fixing the drug delivery elementin the tissue region.
 27. The system of claim 7, wherein the drugdelivery element includes a first electrode thereon adapted to beelectrically coupled to a second electrode, whereby when direct currentis directed between the first and second electrodes, a drug from thedrug delivery element is ionophoretically directed from the drugdelivery element towards the second electrode.
 28. The system of claim27, wherein the second electrode is attachable to a surface region ofthe patient being treated.
 29. The system of claim 7, wherein the drugdelivery element comprises an osmotic surface on the distal portion ofthe catheter.
 30. The system of claim 7, further comprising a feedbacksensor on the drug delivery element or the puncturing element.
 31. Thesystem of claim 30, wherein the feedback sensor comprises an element fordetecting a physiological condition at the tissue region.
 32. The systemof claim 30, wherein the feedback sensor comprises an EKG lead.
 33. Asystem for delivering a drug to a tissue region within a patient's body,the system comprising: a catheter having a proximal portion and a distalportion adapted for insertion into a blood vessel, and defining aperiphery and a longitudinal axis; a needle deployable from the distalportion having a drug delivery lumen therein for delivering drugstherethrough; an orientation element on the distal portion in apredetermined relationship with the needle; and an imaging elementadjacent the orientation element for detecting the location of theorientation element with respect to a tissue region surrounding thedistal portion.
 34. The system of claim 33, wherein the catheterincludes a needle lumen extending from the proximal portion to aperipheral opening at a predetermined circumferential location on theperiphery of the distal portion through which the needle may bedeployed, and the orientation element has an asymmetric configurationaligned with the peripheral opening on the periphery.
 35. The system ofclaim 34, wherein the orientation element comprises a plurality ofstruts extending axially along the distal portion.
 36. The system ofclaim 34, wherein one of the plurality of struts is provided at alocation in direct axial alignment with the peripheral opening.
 37. Thesystem of claim 34, wherein the orientation element comprises aradiopaque marker.
 38. The system of claim 37, wherein the radiopaquemarker comprises a pair of markers disposed opposite one another on theperiphery.
 39. A system for creating a reservoir in a tissue regionwithin a patient's body for receiving a drug therein, the systemcomprising: a catheter having a proximal portion and a distal portionadapted for insertion into a blood vessel, and defining a periphery anda longitudinal axis; a guide wire assembly deployable from the distalportion in a predetermined circumferential relationship with theperiphery of the catheter; an orientation element on the distal portionin a predetermined relationship with the guide wire assembly, theorientation element being detectable by an imaging element for detectingthe location of the orientation element with respect to an extravasculartissue region surrounding the distal portion; and a tissue ablationdevice deployable in combination with the guide wire assembly forforming a cavity in the extravascular tissue region.
 40. The system ofclaim 39, further comprising an imaging element adjacent the orientationelement for detecting the location of the orientation element withrespect to an extravascular tissue region surrounding the distalportion.
 41. A reservoir device for providing sustained delivery of adrug within the cardiovascular system of a patient, comprising: anelongate frame adapted to expand between a collapsed condition forinsertion into a blood vessel and an enlarged condition for engaging awall of the blood vessel, the frame defining a longitudinal axis and aperiphery; and a flexible membrane attached to the frame and defining areservoir therein, the membrane including a porous region.
 42. Thedevice of claim 41, wherein the porous region of the membrane isdisposed along the periphery of the frame.
 43. The device of claim 41,wherein the frame is biased towards the enlarged condition.
 44. Thedevice of claim 41, wherein the porous region comprises a semi-permeablematerial.
 45. The device of claim 41, further comprising a drug withinthe reservoir adapted to pass through the porous region of the membrane.46. The device of claim 45, further comprising an anti-coagulantcompound within the reservoir.
 47. The device of claim 41, wherein anend region of the membrane is penetrable by an injection device tofacilitate in situ filling of the reservoir.
 48. The device of claim 41,further comprising a septum dividing the reservoir into first and secondreservoir regions.
 49. The device of claim 48, wherein the membraneincludes an osmotic region communicating with the first reservoirregion.
 50. The device of claim 49, wherein the porous region of themembrane communicates with the second reservoir region.
 51. A method ofdelivering a selected to a selected tissue region within a patient'sbody with a catheter having a deployable puncturing element, a drugdelivery element and an orientation element on a distal portion thereof,the method comprising: percutaneously introducing the distal portion ofthe catheter into a blood vessel; directing the distal portionendovascularly to a vessel location adjacent to the selected tissueregion; orienting the puncturing element towards the selected tissueregion; deploying the puncturing element to access the selected tissueregion; and delivering a drug with the drug delivery element to theselected tissue region.
 52. The method of claim 51, wherein the bloodvessel comprises a vein.
 53. The method of claim 51, wherein the bloodvessel comprises a coronary vein, and the selected tissue regioncomprises myocardial tissue or a coronary artery.
 54. The method ofclaim 51, wherein the orienting step includes the step of imaging theorientation element.
 55. The method of claim 54, wherein the orientationelement has a predetermined circumferential relationship about aperiphery of the catheter with respect to the puncturing element. 56.The method of claim 54, wherein the catheter includes an imaging elementadjacent the orientation element, and the imaging step includes the stepof operating the imaging element.
 57. The method of claim 56, whereinthe imaging element comprises an ultrasound transducer, and the step ofoperating the imaging element includes the step of obtaining an imageslice including the selected tissue region along a plane substantiallynormal to a longitudinal axis of the catheter.
 58. The method of claim51, wherein the puncturing element comprises a needle, and wherein thedeploying step includes penetrating a wall of the blood vessel andentering the tissue region with a distal tip of the needle.
 59. Themethod of claim 51, further comprising the step of mapping the selectedtissue region prior to the step of delivering a drug.
 60. The method ofclaim 59, wherein the mapping step includes introducing a radiographicagent into the selected tissue region.
 61. The method of claim 51,wherein the delivering step includes the step of deploying the drugdelivery element in combination with the puncturing element.
 62. Themethod of claim 61, wherein the drug delivery element comprises aninfusion catheter.
 63. The method of claim 62, wherein the deliveringstep includes the step of inflating a porous balloon on the infusioncatheter.
 64. The method of claim 51, further comprising the steps of:delivering an ablation element to the tissue region; and activating theablation element to create a drug reservoir within the tissue region.65. The method of claim 64, wherein the step of delivering the ablationelement includes the step of advancing the ablation element over thepuncturing element into the tissue region.
 66. A method of creating afluid reservoir within an extravascular tissue region for sustaineddelivery of a drug using a catheter having a guide wire and anorientation element on a distal portion thereof, the method comprisingthe steps of: percutaneously introducing the distal portion of thecatheter into a blood vessel; directing the distal portionendovascularly to a vessel location adjacent to the tissue region;orienting the guide wire towards the tissue region; deploying the guidewire into the tissue region; and forming a drug reservoir within thetissue region.
 67. The method of claim 66, wherein the blood vesselcomprises a vein.
 68. The method of claim 66, wherein the blood vesselcomprises a coronary vein and the extravascular tissue region comprisesmyocardial tissue.
 69. The method of claim 66, further comprising thestep of introducing a drug into the drug reservoir.
 70. The method ofclaim 66, wherein the step of forming a drug reservoir includes thesteps of delivering an ablation element into the tissue region, andactivating the ablation element to create the drug reservoir.
 71. Themethod of claim 66, further comprising the step of introducing a sealantinto the drug reservoir to seal the drug reservoir from the vessellocation.
 72. The method of claim 66, wherein the step of forming a drugreservoir includes the step of removing a portion of the tissue region.73. A method for creating a drug reservoir within a blood vessel fordelivering a drug to a tissue region adjacent the blood vessel, themethod comprising the steps of: advancing a first endovascular blockerin a collapsed condition along the blood vessel to a location adjacentthe tissue region; expanding the first endovascular blocker to anenlarged condition, thereby sealing the blood vessel at the locationfrom fluid flow along the blood vessel; advancing a second endovascularblocker in a collapsed condition along the blood vessel to the location;expanding the second endovascular blocker to an enlarged condition,thereby further sealing the blood vessel at the location from fluid flowalong the blood vessel; and introducing a drug into the blood vesseladjacent the first endovascular blocker.
 74. The method of claim 73,wherein the step of expanding the second endovascular blocker includesthe step of deploying the second endovascular blocker adjacent to thefirst endovascular blocker, thereby defining a drug reservoir within theblood vessel between the first and second endovascular blockers.
 75. Themethod of claim 73, wherein the introducing step includes the step ofintroducing the drug into the drug reservoir.
 76. The method of claim75, wherein the blood vessel comprises a vein.
 77. The method of claim75, wherein the blood vessel comprises a coronary vein, and wherein thetissue region comprises myocardial tissue or a coronary artery.
 78. Amethod of providing access to a selected tissue region within apatient's body from a blood vessel using a transvascular catheter havinga deployable puncturing element, and an orientation element on a distalportion thereof, the method comprising: percutaneously introducing thedistal portion of the transvascular catheter into a blood vessel;directing the distal portion endovascularly to a vessel locationadjacent to the selected tissue region; orienting the puncturing elementtowards the selected tissue region; deploying the puncturing element toaccess the selected tissue region; advancing a floppy catheter into theselected tissue region; and removing the transvascular catheter from thebody.
 79. The method of claim 78, comprising the additional step ofadvancing a guide wire into the selected tissue region.
 80. The methodof claim 79, wherein the step of advancing a floppy catheter comprisestracking the floppy catheter over the guide wire into the selectedtissue region.
 81. The method of claim 78, comprising the additionalstep of securing a proximal end of the floppy catheter to a surfacelocation of the patient's body.
 82. The method of claim 78, comprisingthe additional step of delivering a drug through the floppy catheterinto the selected tissue region.
 83. The method of claim 78, wherein theblood vessel comprises a vein.
 84. The method of claim 78, wherein theblood vessel comprises a coronary vein, and wherein the selected tissueregion comprises myocardial tissue or a coronary artery.